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Physiol. Genomics (March 26, 2002). doi:10.1152/physiolgenomics.00099.2001
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Articles in PresS, published online ahead of print March 26, 2002
Physiol Genomics, 10.1152/physiolgenomics.00099.2001
Submitted on October 18, 2001
Accepted on March 22, 2002

DIVERGENT ABNORMAL MUSCLE RELAXATION BY HYPERTROPHIC CARDIOMYOPATHY AND NEMALINE MYOPATHY MUTANT TROPOMYOSINS: A CELLULAR BASIS FOR DIFFERENTIAL CLINICAL PHENOTYPES

Daniel E Michele1, Pierre Coutu1, and Joseph M Metzger1*

1 Physiology, University of Michigan, Ann Arbor, MI, USA

* To whom correspondence should be addressed. E-mail: metzgerj{at}umich.edu.

Mutations in tropomyosin have been linked to distinct inherited diseases of cardiac and skeletal muscle, hypertrophic cardiomyopathy (HCM) and nemaline myopathy (NM). How HCM and NM mutations in nearly identical Tm proteins produce the vastly divergent clinical phenotypes of heightened, prolonged cardiac muscle contraction in HCM and skeletal muscle weakness in NM is currently unknown. We report here a direct comparison of the effects of HCM (A63V) and NM (M9R) mutant Tm on membrane intact myocyte contractile function as assessed by adenoviral gene transfer to fully differentiated cardiac muscle cells. Both wild-type, HCM and NM mutant proteins were expressed at similar levels into myocytes, and incorporated into sarcomeres. Interestingly, HCM mutant Tm produced significantly longer contractions by slowing relaxation, whereas NM mutant Tm produced the opposite effect of accelerated muscle relaxation. We propose slowed relaxation caused by HCM mutant Tm can directly contribute to diastolic dysfunction seen in HCM even without secondary cardiac remodeling. Conversely, hastening of relaxation by NM mutant Tm may shift the force-frequency relationship in skeletal muscle and contribute to muscle weakness seen in NM. Together, these results implicate divergent, abnormal "turning off" of muscle contraction, as a cellular basis for the differential pathogenesis of mutant Tm associated HCM and NM.




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